The invention relates to the use of pyridyl aklane, pyridyl alkene and/or pyridyl alkine acid amides, especially in the treatment of tumor conditions and/or as cytostatic agents or as immunosuppressive agents as well as medicaments with an amount of these compounds in combination with other cytostatic agents or immunosuppresive agents.
A strong need exists for the enrichment of cytostatic therapy to provide pharmaceuticals and/or medicaments which not only possess a strong activity, but also exert diminished side effects in comparison to many classical cancerostatic agents, whereby treatment of a broad as possible spectrum of tumors should be made accessible. Furthermore, effective cytostatic agents for an efficient therapy should be made available. Active ingredients of this type should also be exceptionally suitable in the mentioned indications for a combination therapy, be it in connection with other cytostatic agents or with radiation (for example X-rays, radioactive elements, such as cobalt, or linear accelerator. etc.), with operative procedures, heat treatment, etc. As a consequence, further subject-matter of the invention relates to new medicaments in the form of combinations of the compounds defined below and used according to the invention together with other compounds or immunosuppressive agents customary in the therapy of tumors.
In this connection, a strong need also exists in tumor therapy to open up new possibilities which were not usable up to now in these indications, for example for overcoming or preventing resistances.
This object was successfully solved in a completely suprising manner by making available the specially structured pyridyl derivatives defined below.
It was known that various pyridine compounds substituted in a specific manner have pharmacologically useful properties which lie however in completely different indication areas.
Thus, xcfx89-pyridyl alkane and/or alkene amides with anti-allergic activity are described in EP 0 210 782 which are referred to as having a 5-lipoxygenase-inhibiting and anti-histamine action, wherein the amide components of these compounds contain a piperizine or homopiperizine ring and the pyridine ring can be linked together in the 2-, 3- or 4-position. JP 63,179,869 describes further pyridyl amides, xcfx89-pyridyl alkane and alkene amides as anti-allergic effective substances containing a substituted piperidine ring in the amine component. Such compounds with the same properties are mentioned in Chem. Pharm. Bull 37, 100-105 (1989) and in J. Med. Chem. 1989, 583-593.
Pyridyl ureas, pyridyl thioureas and pyridyl carbonamides, wherein the amide portion is bound over an aryl substituted alkyl chain with a piperidine ring or piprazine ring, are described for example in EP-A-0 428 434 or in EP-A-0 512 902 as antagonists of the neurokinin receptor and substance P. Furthermore, pyridyl(alkyl)carbonamides, pyridyl(alkyl)sulfonamides and analogous ureas, wherein the amide portion is bound over an alkyl chain with a piperidine ring are disclosed in EP-A-0 479 601 as active ingredients with anti-arrhythmic properties.
In WO 91/15 485, the production of pyridine-3,5-dicarboxylic acid esters and amides as well as their use for the treatment of tumor conditions is described. These compounds differ from the compounds according to the invention described below in very important structural features, for example by the dicarboxyl grouping on the pyridine ring or the absence of the hydrocarbon chain between the pyridine ring and the amide grouping. The compounds disclosed in WO 89/07 443 in the form of optically pure R(xe2x88x92)-Ni-guldipine and further analogous dihydropyridines with cytotoxic activity have larger structural differences. However, the compounds according to the invention unexpectedly possess a better activity and a wider spectrum of action despite the large structural differences.
Further structurally closely related compounds are represented by the antagonists of the histimine-H1-receptor described in EP-A-0 343 307 which discloses a series of substituted piperidine derivatives without naming concrete examples for special 3-pyridyl substitutions.
EP-A-0 330 026 also discloses substituted piperidine derivatives with possible, generic pyridyl substitutions for which, however, merely a single concrete example is disclosed, namely (E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide hydrochloride. These compounds are distinguished by an anti-cholinesterase activity, an anti-amnesia activity as well as activities directed against hyperkinesia, senile demensia, mania and Alzheimer""s disease.
In view of this art, the finding that the compounds according to the general formula (I) defined below have activities which make them particularly suitable in an excellent manner for the therapy of tumor illnesses was completely unexpected. Equally unexpected was the pharmacological finding that the compounds according to the invention also possess immunosuppressive properties besides cytostatic activity.
Considering the above-mentioned completely different known medical indications of known piperidine derivatives, such as neurokinin receptor antagonism, hyperkineses, amnesias, allergies, or rhythm disorders, the activity of the compounds used according to the invention with the structural modifications as they are defined below with respect to the present general formula, and the combinations according to the invention in the form of the detected excellent cytostatic or immunomodulatory activity with advantageous therapeutic properties was completely surprising for the person skilled in the art.
Pharmacological test results from which this conclusion must be drawn, as well as the concrete tumor indications and combination possibilities are detailed and illustrated in the last part of the description.
Therefore, subject-matter of the invention relates to the use of one or more compounds of formula (I) 
wherein
R1 is hydrogen, halogen, cyano, trifluoromethyl, hydroxy, benzyloxy, aminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, alkyl, especially C1-C6-alkyl, alkenyl, especially C3-C6-alkenyl, alkinyl, especially C3-C6-alkinyl, hydroxyalkyl, especially C1-C6-hydroxyalkyl, alkoxy, especially C1-C6-alkoxy, alkenyloxy, especially C3-C6-alkenyloxy, alkinyloxy, especially C3-C6-alkinyloxy, alkanoyloxy, especially C1-C7-alkanoyloxy, alkoxycarbonyloxy, especially C2-C7-alkoxycarbonyloxy, alkylthio, especially C1-C6-alkylthio, alkenylthio, especially C3-C6-alkenylthio, alkinylthio, especially C3-C6-alkinylthio, cycloalkyl, especially C3-C8-cycloalkyl, cycloalkyloxy, especially C3-C8-cycloalkyloxy, cycloalkylthio, especially C3-C8-cycloalkylthio, alkoxycarbonyl, especially C2-C7-alkoxycarbonyl, alkylaminocarbonyl, especially C2-C7-alkylaminocarbonyl, dialkylaminocarbonyl, especially C3-C13-dialkylaminocarbonyl, or NR5R6, wherein
R5 and
R6 are selected independently of each other from hydrogen, alkyl, especially C1-C6-alkyl, alkenyl, especially C3-C6-alkenyl and alkinyl, especially C3-C6-alkinyl,
R2 is hydrogen, halogen, cyano, hydroxy, trifluoromethyl, benzyloxy, alkyl, especially C1-C6-alkyl, alkoxy, especially C1-C6-alkoxy or alkanoyloxy, especially C1-C7-alkanoyloxy, wherein R1 and R2, if they are adjacent, optionally form a bridge which is selected from xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CHxe2x95x90CH)2xe2x80x94 and xe2x80x94CH2Oxe2x80x94CR7R8xe2x80x94Oxe2x80x94, wherein
R7 and
R8 are, independently of each other, hydrogen or alkyl, especially C1-C6-alkyl,
R3 is hydrogen, halogen, alkyl, especially C1-C6-alkyl, trifluoromethyl or hydroxyalkyl, especially C1-C6-hydroxyalkyl and
R4 is hydrogen, hydroxy, benzyloxy, alkyl, especially C1-C6-alkyl, alkenyl, especially C3-C6-alkenyl, alkinyl, especially C3-C6-alkinyl, cycloalkyl, especially C3-C6-cycloalkyl or alkoxy, especially C1-C6-alkoxy,
k is 0 or 1,
A is alkylene, especially C1-C6-alkylene, which is optionally substituted once to three-fold by alkyl, especially C1-C3-alkyl, hydroxy, alkoxy, especially C1-C3-alkoxy, fluorine or phenyl, or
1,2-cyclopropylene or
alkenylene with at least two C-atoms, especially C2-C6-alkenylene, which is optionally substituted once to three-fold by C1-C3-alkyl, hydroxy, C1-C3-alkoxy, fluorine, cyano or phenyl,
alkadienylene with at least four C-atoms, especially C4-C6-alkadienylene, which is optionally substituted once or twice by C1-C3-alkyl, fluorine, cyano or phenyl,
1,3,5-hexatrienylene, which is optionally substutited by C1-C3-alkyl, fluorine, cyano, or phenyl,
ethinylene or
alkylene with at least two C-atoms, especially C2-C6-alkylene in which a methylene unit can be isosterically replaced by O, S, NR9, CO, SO or SO2, wherein the isosteric substitution, with the exception of xe2x95x90CO, cannot be adjacent to the amide group and wherein
R9 is selected from hydrogen, alkyl, especially C1-C6-alkyl, alkenyl, especially C3-C6-alkenyl, alkinyl, especially C3-C6-alkinyl, acyl, especially C1-C6-acyl or alkylsulfonyl, especially C1-C6-alkylsulfonyl,
D is selected from alkylene, especially C1-C10-alkylene, optionally substituted once or twice by alkyl, especially C1-C6-alkyl, hydroxy, or alkoxy, especially C1-C6-alkoxy,
alkenylene with at least two C-atoms, especially C2-C10-alkenylene, which is optionally substituted once or twice by alkyl, especially C1-C6-alkyl, hydroxy, or alkoxy, especially C1-C6-alkoxy, wherein the double bond can also be to ring E,
alkinylene with at least three C-atoms, especially C3-C10-alkinylene, optionally substituted once or twice by alkyl, especially C1-C6-alkyl, hydroxy or alkoxy, especially C1-C6-alkoxy, and
alkylene, especially C1-C10-alkylene, alkenylene with at least two C-atoms, especially C2-C10-alkenylene or alkinylene with at least three C-atoms, especially C3-C10-alkinylene, whereby one to three methylene units are each isosterically replaced by O, S, NR10, CO, SO or SO2 wherein
R10 has the same meaning as
R9 but is selected independently thereof,
E is selected from 
wherein the heterocyclic ring can also optionally have a double bond and
n and
p can be, independently of one another, 0, 1, 2 or 3, with the proviso that n+pxe2x89xa64 and
q is 2 or 3,
R11 is hydrogen, alkyl, especially C1-C6-alkyl, hydroxy, hydroxymethyl, carboxy or alkoxycarbonyl with at least two C-atoms, especially C2-C7-alkoxycarbonyl and
R12 is hydrogen, alkyl, especially C1-C6-alkyl or an oxo group adjacent to the nitrogen atom, wherein
R11 and R12 optionally together, form an alkylene bridge with 1, 2, 3, 4 or 5 C-atoms, especially a C1-C3-alkylene bridge under formation of a bicyclic ring system,
G is selected from hydrogen, G1, G2, G3, G4 and G5, wherein
G1 represents the residue
xe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G1)
wherein
r is an integer from 1 to 3 or 0 and
s is 0 or 1,
R13 is selected from hydrogen, alkyl, especially C1-C6-alkyl, alkenyl with at least three C-atoms, especially C3-C6-alkenyl, alkinyl with at least three C-atoms, especially C3-C6-alkinyl, cycloalkyl with at least three C-atoms, especially C3-C8-cycloalkyl,
saturated, five to seven membered heterocycles, which can contain one or two hetero-atoms from the group N and/or S and/or O,
benzyl or phenyl,
monocyclic aromatic five or six-membered heterocycles, which can contain one to three hetero-atoms from the group N and/or S and/or O and are either bound directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
R14 has the same meaning as R13, but is selected independently thereof,
R15 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,
monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected from the group N and/or S and/or O and are either bound directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
G2 is the residue 
wherein the substituents R13 and R15 can have the above meaning or the grouping
xe2x80x94NR13R15
can also be a nitrogen heterocycle bound over the nitrogen atom, selected from
saturated or unsaturated monocyclic, four- to eight-membered heterocycles, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from the group N and/or S and/or O, or
saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from the group N and/or S and/or O,
G3 is the residue
xe2x80x94SO2xe2x80x94(CH2)rR13xe2x80x83xe2x80x83(G3)
and
G4 is the residue 
wherein
Ar1 and Ar2 are selected independently from one another from phenyl, pyridyl or naphthyl and
G5 is the residue
xe2x80x94COR16xe2x80x83xe2x80x83(G5)
wherein
R16 is selected from trifluoromethyl, alkoxy, especially C1-C6-alkoxy, alkenyloxy, especially C3-C6-alkenyloxy, or benzyloxy,
wherein any aryl residues and/or aromatic ring systems in the substituents R1, R2, R4, R13, R14, R15, R16, Ar1 and Ar2 and/or in the ring system xe2x80x94NR13R15 can be substituted independently from each other by one to three of the same or different residues which are selected from halogen, cyano, alkyl, especially C1-C6-alkyl, trifluoromethyl, cycloalkyl, especially C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, alkoxyl, especially C1-C6-alkoxy, alkoxy, substituted entirely or partially by fluorine, substituted alkoxy, especially C1-C6-alkoxy, benzyloxy, phenoxy, mercapto, alkylthio, especially C1-C6-akylthio, carboxy, alkoxycarbonyl, especially C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, monoalkylamino, especially mono-C1-C6-alkylamino, dialkylamino, especially di-(C1-C6-alkyl)-amino and methylenedioxy for two adjacent groups on the aromatic ring or ring system,
wherein each of the residues alkyl, alkenyl, alkinyl, hydroxyalkyl, alkoxy, alkenyloxy, alkinyloxy, alkanoyloxy, alkoxycarbonyl, alkoxycarbonyloxy, alkylthio, alkenylthio, alkinylthio, alkylene, acyl, alkylsulfonyl, alkenylene, alkinylene, cycloalkyl, cycloalkyloxy, alkoxycarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl of the substituents R1 to R14 can have 1 to 2 or 4, 6, 8, 10 or 12 C-atoms and/or 2 or 3 to 5, 7, 9, 11 or 13 and/or 15 C-atoms or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 C-atoms depending on the structure, as well as
stereoisomers and/or mixtures thereof and pharmacologically acceptable
acid addition salts thereof
for the production of medicaments for cytostatic or immunomodulatory and/or immunosuppressive treatment.
A preferred embodiment according to the invention relates to the use of compounds of formula (I) 
for the production of medicaments for the indications named above, wherein in the general formula (I)
R1 is a hydrogen, halogen, cyano, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, trifluoromethyl, C3-C8-cycloalkyl, C1-C6-hydroxyalkyl, hydroxy, C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkinyloxy, benzyloxy, C1-C7-alkanoyloxy, C2-C7-alkoxycarbonyloxy, C1-C6-alkylthio, C3-C6-alkenylthio, C3-C6-alkinylthio, C3-C8-cycloalkyloxy, C3-C8-cycloalkylthio, C2-C7-alkoxycarbonyl, aminocarbonyl, C2-C7-alkylaminocarbonyl, C3-C13-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy, pyridylthio, or NR5R6, wherein
R5 and
R6 are selected independently from each other from hydrogen, C1-C6-alkyl, C3-C6-alkenyl and C3-C6-alkinyl,
R2 is hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, hydroxy, C1-C6-alkoxy, benzyloxy or C1-C7-alkanoyloxy,
wherein R1 and R2, in case they are adjacent, optionally form a bridge which is selected from the bridge members xe2x80x94(CH2)4xe2x80x94 and xe2x80x94(CHxe2x95x90CH)2xe2x80x94 and xe2x80x94CH2Oxe2x80x94CR7R8xe2x80x94Oxe2x80x94, wherein
R7 and
R8 are, independently from each other, hydrogen or C1-C6-alkyl,
R3 is hydrogen, halogen, C1-C6-alkyl, trifluoromethyl or C1-C6-hydroxyalkyl and
R4 is hydrogen, C1-C 6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C6-cycloalkyl, hydroxy, C1-C6-alkoxy or benzyloxy,
k is 0 or 1,
A is C1-C6-alkylene, which is optionally substituted once to three-fold by C1-C3-alkyl, hydroxy, C1-C3-alkoxy, fluorine or phenyl, or
1,2-cyclopropylene or
C2-C6-alkenylene, which is optionally substituted once to three-fold by C1-C3-alkyl, hydroxy, C1-C3-alkoxy, fluorine, cyano or phenyl,
C4-C6-alkadienylene, which is optionally substituted once or twice by C1-C3-alkyl, fluorine, cyano or phenyl
1,3,5-hexatrienylene, which is optionally substituted by C1-C3-alkyl, fluorine, cyano or phenyl
ethynylene or
C2-C6-alkylene, wherein a methylene unit can be isosterically replaced by O, S, NR9, CO, SO or SO2, wherein the isosteric substitution, with the exception of xe2x95x90CO, cannot be adjacent to the amide group, and
R9 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C1-C6-acyl or C1-C6-alkylsulfonyl,
D is selected from C1-C10-alkylene, optionally substituted once or twice by C1-C6-alkyl, hydroxy or C1-C6-alkoxy,
C2-C10-alkenylene, which is optionally substituted once or which by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy, wherein the double bond can also be to ring E,
C3-C10-alkinylene, optionally substituted once or twice by C1-C6-alkyl, hydroxy, or C1-C6-alkoxy, and
C1-C10-alkylene, C2-C10-alkenylene or C3-C10-alkinylene, wherein one to three methylene units are each isosterically replaced by O, S, NR10, CO, SO or SO2, wherein
R10 has the same meaning as R9, but is selected independently therefrom,
E is selected from 
wherein the heterocyclic ring can optionally have a double bond and
n and
p can be, independently of each other, 0, 1, 2 or 3, with the proviso that n+pxe2x89xa64 and
q is 2 or 3,
R11 is hydrogen, C1-C6-alkyl, hydroxy, hydroxymethyl, carboxy or C2-C7-alkoxycarbonyl and
R12 hydrogen, C1-C6-alkyl or an oxo group adjacent to the nitrogen atom, wherein
R11 and R12 optionally together form a C1-C3-alkylene bridge under formation of a bi-cyclic ring system,
G is selected from hydrogen,
G1, G2, G3, G4 and G5, wherein
G1 represents the residue
xe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G1)
wherein
r is an integer from 1 to 3 or 0 and
s is 0 or 1,
R13 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C8-cycloalkyl,
saturated, five- to seven-membered heterocycles, which can contain one or two hetero-atoms from the group N and/or S and/or O,
benzyl or phenyl,
monocyclic aromatic five or six-membered heterocycles, which can contain one to three hetero-atoms from the group N and/or S and/or O and are either bound directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group,
R14 has the same meaning as R13, but is selected independently thereof,
R15 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,
monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected from the group N and/or S and/or O and are either bound directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein the linkage can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from N and/or S and/or O and the linkage can occur either over an aromatic ring or a hydrated ring and either directly or over a methylene group.
G2 is the residue 
wherein the substituents R13 and R15 can have the above meaning or the grouping
xe2x80x94NR13R15
can also be a nitrogen heterocycle bound over the nitrogen atom, selected from
saturated or unsaturated monocyclic, four- to eight-membered heterocycles, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from the group N and/or S and/or O, or
saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from the group N and/or S and/or O,
G3 is the residue
xe2x80x94SO2xe2x80x94(CH2)rR13xe2x80x83xe2x80x83(G3)
and
G4 is the residue 
wherein
Ar1 and Ar2 are selected independently from one another from phenyl, pyridyl or naphthyl and
G5 is the residue
xe2x80x94COR16xe2x80x83xe2x80x83(G5)
wherein
R16 is selected from trifluoromethyl, C1-C6-alkoxy, C3-C6-alkenyloxy, or benzyloxy, and wherein
aromatic ring systems in the substituents R1, R2, R4, R13, R14, R15, R16, Ar1 and Ar2 and/or in the ring system xe2x80x94NR13R15 can be substituted independently from each other by one to three of the same or different residues which are selected from halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-Cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, which can optionally be entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino or di-(C1-C6-alkyl)-amino and methylenedioxy for trio adjacent groups on the aromatic ring or ring system,
stereoisomers thereof and/or mixtures thereof and pharmacologically acceptable acid addition salts.
A further preferred embodiment of the invention constitutes the use of compounds for the indications named above, which are distinguished in that substituents R1, R2, R3, R4, R5, R6, R7, R8 R9, R10, R13, R14, R15 and R16 as well as A and D indicated for formula (I) have the following meaning in connection with the given substitutions according to this formula 
wherein
halogen is fluorine, chlorine, bromine or iodine,
C1-C6-alkyl can be straight chain or branched and is preferably a methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert-butyl-, cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl-, neopentyl-, cyclopropylethyl-, cyclobutylmethyl- or a hexyl group,
alkylene is for example methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene,
C3-C6-alkenyl can be straight chain or branched and is preferably an allyl-, 2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-, 2-pentenyl-, 4-pentenyl-, 2-methyl-2-butenyl-, 3-methyl-2-butenyl-, 2-hexenyl-, 5-hexenyl-, 4-methyl-3-pentenyl- or 2,2-dimethyl-3-butenyl group,
alkenylene is for example ethenylene, propenylene, butenylene, pentenylene, hexenylene, hexathenylene, heptenylene, octenylene, nonenylene or decenylene,
C3-C6-alkinyl can be straight chain or branched and is preferably a propargyl-, 2-butinyl-, 3-butinyl-, 4-pentinyl-, 5-hexinyl- or 4-methyl-2-pentinyl group,
alkinylene is for example propinylene, butinylene, pentinylene, hexinylene, heptinylene, octinylene, noninylene or decinylene,
C3-C8-cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
C1-C6-hydroxyalkyl contains a hydroxyl group in one of the above-named C1-C6-alkyl residues, especially in the form of the hydroxymethyl- and hydroxyethyl group, wherein
C1-C6-alkoxy, C3-C6-alkenyloxy, C3-C6-alkinyloxy each contain, aside from the oxygen atom, one of the C1-C6-alkyl-, C3-C6-alkenyl- and/or C3-C6-alkinyl groups named above and the methoxy)-, ethoxy-, isopropoxy-, tert-butoxy-, allyloxy- and propargyloxy group are preferred and is to be understood as among C1-C6-alkoxy entirely or partially substituted with fluorine, for example difluormethoxy, trifluormethoxy or 2,2,2-trifluorethoxy,
C1-C6-alkylthio. C3-C6-alkenylthio, C3-C6-alkinylthio each contain, aside from the sulfur atom, one of the C1-C6-alkyl-, C3-C6-alkenyl- or C3-C6-alkinyl group named above, especially the methylthio-, ethylthio-, isopropylthio- and tert-butylthio groups,
C3-C8-cycloalkyloxy and C3-C8-cycloalkylthio are preferred as cyclopentyloxy- and cyclopentylthio- and/or cyclohexyloxy- and cyclohexylthio groups,
C1-C7-alkanoyloxy groups contain, aside from the oxygen atom, an aliphatic acyl residue with 1 to 7 carbon atoms, especially the acetoxy-, propionyloxy- and pivaloyloxy group,
C2-C7-alkoxycarbonyl groups contain, aside from the carbonyl group, one of the C1-C6-alkoxy groups mentioned above, especially the methoxycarbonyl-, ethoxycarbonyl-, isopropoxycarbonyl-, isobutoxycarbonyl- and tert-butoxycarbonyl group,
C2-C7-alkoxycarbonyloxy groups contain, aside from the oxygen atom, one of the C2-C7-alkoxycarbonyl residues mentioned above, especially the methoxycarbonyloxy-, ethoxycarbonyloxy-, isopropoxycarbonyloxy-, isobutoxycarbonyloxy- and tert-butoxycarbonyl group as well as the allyloxycarbonyloxy group,
C2-C7-alkylaminocarbonyl and C3-C13-dialkylaminocarbonyl groups contain, beside the carbonyl group, an alkylamino- and/or dialkylamino residue, whose C1-C6-alkyl groups have the above meanings, wherein the dimethylaminocarbonyl-, diethylaminocarbonyl- and the diisopropylaminocarbonyl groups are preferred, and aside from the unsubstituted amino group, one of the following C1-C6-alkylamino groups and/or di-(C1-C6-alkyl)amino groups are to be understood under the amino groups of the formula NR5R6,
C1-C6-alkylamino contains one of the C1-C6-alkyl groups mentioned above, especially in form of the methylamino-, ethylamino-, propylamino-, isopropylamino-, butylamino- and the tert-butylamino group,
di-(C1-C6-alkyl)amino carries two of the same or different of the above named C1-C6-alkyl groups on the nitrogen atom, especially in form of the dimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-, isopropylmethylamino-, dibutylamino- or tert-butylmethylamino group,
C1-C6-acyl is the residue of an aliphatic saturated or unsaturated, straight chain, branched or cyclic carboxylic acid, especially in form of the formyl-, acetyl-, propionyl-, acryloyl-, butyryl-, isobutyryl-, methacryloyl-, cyclopropylcarbonyl-, pentanoyl-, pivaloyl-, cyclobutylcarbonyl-, hexanoyl- and the dimethylacryloyl group,
C1-C6-alkansulfonyl is preferably the methanesulfonyl-, ethanesulfonyl-, propanesulfonyl-, butanesulfonyl-, pentanesulfonyl- and the hexanesulfonyl group,
saturated five- to seven-membered heterocycles with one or two hetero-atoms are especially tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, hexahydroazepinyl, piperazinyl, hexahydrodiazepinyl or morpholinyl,
monocyclic aromatic five- or six-membered heterocycles with one to three hetero-atoms are especially furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl or triazinyl,
anellated bi- and tricyclic aromatic or partially hydrated carbocyclc ring systems with 8 to 16 ring atoms and at least one aromatic ring are preferably benzocyclobutyl, indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluorenyl, anthryl, dihydroanthryl, phenanthryl, dihydrophenanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl, wherein mono- or dioxo-derivates, wherein the residues of indanone, tetralone, anthrone, anthraquinone, fluorenone, phenanthrone, dibenzocycloheptenone, dihydrodibenzocycloheptenone or tetrahydrodibenzocyclooctenone are for example also to be understood as partially hydrated carbocyclic ring systems,
anellated bi- and tricyclische aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring are, for example, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl, benzopyranyl, quinolyl, isoquinolyl, dihydroquinolyl, tetrahydroquinolyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, pyridoindolyl, acridinyl, phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl, dihydropnridobenzoxepinyl, dihydropyridobenzoxazepinyl, dihydrodibenzothiazepinyl or dihydropyridobenzothiazepinyl, wherein their mono- or dioxo-derivates and/or optionally their possible tautomeres are also to be understood as partially hydrated heterocyclic ring systems, for example, the residues of indolinone, isatin, benzoxazol one and/or its tautomeres hydroxybenzoxazol, of benzisoxazolone, benzothiazolone, benzoisothiazolone and benzimidazolone and/or their tautomeres, hydroxybenzisoxazol, hydroxybenzothiazol, hydroxybenzoisothiazol and hydroxybenzimidazol, of indazolinone, of oxazolopyridinone, thiazolopyridinones, pyrazolopyridinones and imidazopyridinones and/or their tautomeres hydroxyoxazolopyridine, hydroxythiazolopyridines, hydroxypyrazolopyridines and hydroxyimidazopyridines, the residues of chromanone, chromone, quinolinone, di-hydroquinolinone, tetrahydrocarbazolone, acridone, of dihydrodibenzoxepinones, benzocycloheptathiophenones, dihydrothienobenzothiepinones, dihydrodibenzothiepinones, dihydrodibenzoazepinones, benzocycloheptapyridinones, dihydropyridobenzoxazepinones, dihydrodibenzothiazepinones and of dihydropyridobenzothiazepinones,
saturated and unsaturated monocyclic, four- to eight-membered heterocycles are xe2x80x94NR13R15 as a grouping which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O, for example azetidine, pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine, (1H)tetrahydroazepine, octahydroazocine, pyrazolidine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine or thylomorpholine-1,1-dioxide,
saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, represent xe2x80x94NR13R15 as a grouping which, aside from the essential nitrogen atom optionally contain one or two further hetero-atoms, selected from N and/or S and/or O, for example 5-aza-bicyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.2]octane, 9-aza-bicyclo[3.3.1]nonane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine, (4H)-dihydrobenothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)-dihydroacridine, 1,2,3,4-tetrahydroacridanone, (10H)-phenoxazin, (10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine, (5H)-octahydrodibenzazepine, (5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydro-dibenzo[b,f]oxazepine, (10H)-dihydrodibenzo[b,f]thiazepine or (5H)-tetrahydrodibenzazocine, as well as optionally possible
tautomeres in the case of substitution of the heterocycle as such or in an anellated ring system by free hydroxy-, mercapto- and/or amino groups, and their
stereoisomers such as, if applicable, cis/trans-isomers, endo/exo-isomers, optic isomers such as enantiomers, diastereomers as pure isomers or mixtures and/or racemic mixtures as well as the pharmacologically acceptable acid addition salts with inorganic or organic acids, wherein the hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates, are preferred as addition salts with suitable inorganic acids and acetates, benzoates, 4-methoxaybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, ascorbate, salicylate, formiate, glutarate, tricarballylate, citrates, fumarates, gluconates, malates, maleates, methanesulfonates, lactates, oxalates, succinates, tartrates and toluolsulfonates, for example p-toluolsulfonate are preferred as addition salts of organic acids.
The use of compounds in which the substitutents labelled in formula (I) 
have the following, meanings, are especially preferred
R1 is hydrogen, halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, C1-C4-hydroxyalkyl, hydroxy, C1-C4-alkoxy, benzyloxy, C1-C4-alkanoyloxy, C1-C4-alkylthio, C2-C5-alkoxycarbonyl, aminocarbonyl, C3-C9-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, pyridyloxy or NR5R6, wherein
R5 and
R6 are selected independently from each other form hydrogen and C1-C6-alkyl,
R2 is hydrogen, halogen, C1-C6-alkyl, trifluoromethyl or hydroxy, wherein
R1 and R2, in the case they are adjacent, optionally form a bridge which are selected from the group of bridge members xe2x80x94(CH2)4xe2x80x94 and xe2x80x94(CHxe2x95x90CH)2xe2x80x94 and xe2x80x94CH2Oxe2x80x94CR7R8xe2x80x94Oxe2x80x94, wherein
R7 and
R8 can be, independently from each other, hydrogen and C1-C6-alkyl,
R3 is selected from hydrogen, halogen and C1-C6-alkyl and
R4 is selected from hydropgen, C1-C6-alkyl, C3-C6-alkenyl, hydroxy, C1-C6-alkoxy and benzyloxy,
k is 0 or 1,
A is C1-C6-alkylene, which is optionally substituted once to three-fold by C1-C3-alkyl, hydroxy, fluorine or phenyl,
1,2-cyclopropylene,
C2-C6-alkenylene, which is optionally substituted one to three-fold by C1-C3-alkyl, hydroxy, fluorine, cyano, or phenyl,
C4-C6-alkadienylene, which is optionally substituted once or twice by C1-C3-alkyl, fluorine, cyano, or phenyl,
1,3,5-hexatrienylene, which is optionally substituted by C1-C3-alkyl, fluorine, or cyano,
ethinylene or
C2-C6-alkylene, wherein a methylene unit can be isosterically replaced by O, S, NR9, CO, SO or SO2, and wherein the isosteric substitute, with the exception of xe2x95x90CO, cannot be adjacent to the amide group, and wherein
R9 is hydrogen, C1-C3-alkyl, C1-C6-acyl or methanesulfonyl,
D is selected from C1-C10-alkylene, which is optionally substituted once or twice by C1-C3-alkyl or hydroxy,
C2-C10-alkenylene, optionally substituted once or twice by C1-C3-alkyl or hydroxy, wherein the double bond can also be to ring E or
C3-C10-alkinylene, which is optionally substituted once or twice by C1-C3-alkyl or hydroxy, and can be selected as well from
C1-C10-alkylene, C2-C10-alkenylene or C3-C10-alkinylene, in which one to three methylene units are isosterically replaced by O, S, NR10, CO, SO or SO2, wherein
R10 has the same meaning as R9, but is selected independently therefrom,
E is 
wherein the heterocyclic ring can optionally have a double bond and
n and p can be, independent of each other, 0, 1, 2 or 3, with the proviso that n+pxe2x89xa64,
q is 2 or 3,
R11 is selected from hydrogen, C1-C3-alkyl, hydroxy, hydroxymethyl, carboxy or C2-C7-alkoxycarbonyl and
R12 is selected from hydrogen or an oxo group adjacent to the nitrogen atom,
G is selected from hydrogen, G1, G2, G3, G4 and G5, wherein
G1 represents the residue
xe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G1)
wherein
r is 0, 1 or 2 and
s is 0 or 1,
R13 is selected from hydrogen, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C8-cycloalkyl,
benzyl, phenyl,
monocyclic aromatic five- or six-membered heterocycles, which contain one to three hetero-atoms from the group N and/or S and/or O and are either bound directly or over a methylene group, anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, whereby the bond can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from the groups N and/or S and/or O and the bond can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
R14 has the same meaning as R13, but is selected independently thereof,
R15 is selected from hydrogen, hydroxy, methyl, benzyl or phenyl,
monocyclic aromatic five- or six-membered heterocycles, which can contain one to three hetero-atoms selected from the group N and/or S and/or O and are bound either directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated carbocyclic ring systems with 8 to 16 ring atoms and at least einem aromatic ring, wherein the bond can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
anellated bi- and tricyclic aromatic or partially hydrated heterocyclic ring systems with 8 to 16 ring atoms and at least one aromatic ring, wherein one to three ring atoms can be selected from the group N and/or S and/or O and the bond can occur either over an aromatic or a hydrated ring and either directly or over a methylene group,
G2 is selected from the residues 
wherein the substituents R13 and R15 the can have the above meaning, or the grouping
xe2x80x94NR13R15
can also be a nitrogen heterocycle bound over the nitrogen atom, selected from
saturated or unsaturated monocyclic, four- to eight-membered heterocycles, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O, or
saturated or unsaturated bi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms, which, aside from the essential nitrogen atom, can optionally contain one or two further hetero-atoms selected from N and/or S and/or O,
G3 is the residue
xe2x80x94SO2xe2x80x94(CH2)rR13xe2x80x83xe2x80x83(G3),
G4 is the residue 
wherein
Ar1 and
Ar2 are selected independently of each other from phenyl, pyridyl or naphthyl,
G5 is the residue
xe2x80x94COR16xe2x80x83xe2x80x83(G5)
wherein
R16 is trifluoromethyl, C1-C6-alkoxy, C3-C6-alkenyloxy or benzyloxy and
aromatic ring systems in which the substituents R1, R2, R4, R13, R14, R15, R16, Ar1 and Ar2 and/or in the ring system xe2x80x94NR13R15 can carry independently of each other one to three of the same or different substituents from the series halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, which is optionally entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)-amino, wherein two adjacent groups on the aromatic ring or ring system can form an additional ring over a methylenedioxy bridge.
The use of compounds in which the substiutents labelled in formula (I) 
have the following meanings are particularly preferred:
R1 is hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy, C1-C4-alkoxy, ethylthio, methoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, carboxy, and phenoxy,
R2 is hydrogen, halogen, trifluoromethyl or hydroxy,
R3 is hydrogen or halogen,
R4 is selected from hydrogen, C1-C3-alcyl, hydroxy and C1-C3-alkoxy,
k is 0 or 1,
A is C2-C6-alkylene, which is optionally substituted once or twice by C1-C3-alkyl, hydroxy or fluorine, as well as
C2-C6-alkenylene, which is optionally substituted once or twice by C1-C3-alkyl, hydroxy or fluorine
C4-C6-alkadienylene, which is optionally substituted by is C1-C3-alkyl or by one or two fluorine atoms,
1,3,5-hexatrienylene, which is optionally substituted by fluorine, or
C2-C6-alkylene, wherein a methylene unit can be isosterically replaced by O, S, CO or SO2, and the isosteric substitute, with the exception of xe2x95x90CO, cannot be adjacent to the amide group and,
D is C1-C8-alkylene, which is optionally substituted once twice by methyl or hydroxy,
C2-C8-alkenylene, which is optionally substituted once or twice by methyl or hydroxy, wherein the double bond can also be to ring E,
C3-C8-alkinylene, which is optionally substituted once or twice by methyl or hydroxy, as well as
C1-C8-alkylene, C2-C8-alkenylene or C3-C8-alkinylene, in which one to three methylene units can be isosterically replaced by O, S, NH, N(CH3), N(COCH3), N(SO2CH3), CO, SO or SO2,
E is 
wherein the heterocyclic ring can optionally have a double bond and
n and
p can be independent of each other 0, 1, 2 or 3, with the proviso that n+pxe2x89xa63,
q is 2 or 3,
R11 is selected from hydrogen, C1-C3-alkyl, hydroxy, hydroxymethyl and
R12 is selected from hydrogen or an oxo group which is adjacent to the nitrogen atom,
G is hydrogen or G1, G2, G3, G4 and G5, wherein
G1 represents the residue
xe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G1)
wherein
r is 0, 1 or 2 and
s is 0 or 1,
R13 is selected from hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, benzyl or phenyl,
benzocyclobutyl, indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl, biphenylenyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, phenanthryl, dihydrophenanthryl, oxodihydrophenanthryl, dibenzocycloheptnyl, oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl. oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl, tetrahydrodibenzocyclooctenyl and oxotetrahydrodibenzocyclooctenyl, bound directly or over a methylene group,
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazoly,l, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl, indazolyl, oxoindazolinyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl, oxodihydropyrazolopyridyl, thienopyrimidinyl, chromanyl, chromanonyl, benzopyranyl, chromanyl, quinolyl, isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl, oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl, oxodihydrodibenzoxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl, oxodihydrothienobenzothiepinyl dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, octahydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl, dihydropyridobenzoxazepinyl, oxodihydropyrdobenzoxazepinyl, dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl, dihydropyridobenzothiazepinyl, oxodihydropyridobenzothiazepinyl, bound directly or over a methylene group,
R14 has the same meaning as R13, but is selected independently therefrom,
R15 is selected from hydrogen, hydroxy, methyl, benzyl or phenyl, indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, benzofuryl, benzothienyl, indolyl, indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl bound directly or over a methylene group,
G2 is selected from the residues 
wherein the substituents R13 and R15 can have the above meanings, or represents the grouping
xe2x80x94NR13R15
each over the nitrogen-bound ring atom of azetidine, pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine, (1H)tetrahydroazepine, octahydroazocine, pyrazolidine, piperazine, hexyhydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine, thiomorpholine-1,1-dioxide, 5-aza-bi-cyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, 9-azabicyclo[3.3.1]nonane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, (10H)-dihydroacridine, 1,2,3,4-tetrahydroacridanone, (10H)-phenoxazine, (10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine, (5H)-Octahydrodibenzazepine, (5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[b,f]oxazepine, (10H)-dihydrodibenzo[b,f]thiazepine or (5H)-tetrahydrodibenzazocine,
G3 is the residue
xe2x80x94SO2xe2x80x94(CH2)rR13xe2x80x83xe2x80x83(G3),
G4 is the residue 
wherein
Ar1 and
Ar2 are selected independently of each other from phenyl, pyridyl or naphthyl,
G5 is the residue
xe2x80x94COR16xe2x80x83xe2x80x83(G5)
wherein
R16 is trifluoromethyl, C1-C6-alkoxy, C3-C6-alkenyloxy or benzyloxy and
aromatic ring systems in which the substituents can be substituted independently of each other by one to three of the same or different substituents from the series halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-Cycloalkyl phenyl, benzyl, hydroxy, C1-C6-alkoxy, C1-C6-alkoxy, which can be entirely or partially substituted by fluorine, can carry benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino, di-(C1-C6-alkyl)-amino, wherein two adjacent groups in the ring or ring system can form an additional ring over a methylenedioxy bridge.
A further preferred embodiment of the invention is in the use of compounds which are distinguished in that the labelled substituents in formula (I) 
have the following meaning:
R1 is hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy, methoxy or methoxycarbonyl,
R2 is hydrogen or halogen,
R3 is hydrogen,
R4 is selected from hydrogen, C1-C3-alkyl or hydroxy,
k is 0 or 1,
A is selected from C2-C6-alkylene, which is optionally substituted once or twice by hydroxy or fluorine, or
C2-C6-alkenylene, which is optionally substituted once or twice by hydroxy or fluorine,
C4-C6-alkadienylene, which is optionally substituted by one or two fluorine atoms,
1,3,5-hexatrienylene or
C2-C6-alkylene, wherein a methylene unit can be isosterically replaced by O, S or CO, and the isosteric substitute, with the exception of xe2x95x90CO, cannot be adjacent to the amide group and,
D is C2-C8-alkylene, which is optionally substituted by methyl or hydroxy,
C2-C8-alkenylene, which is optionally substituted by methyl or hydroxy, wherein the double bond can also be to ring E, or
C2-C8-alkylene, C2-C8-alkenylene, wherein one to three methylene units can be isosterically replaced by O, NH, N(CH3), N(COCH3), N(SO2CH3) or CO,
E is selected from the residues 
wherein the heterocyclic ring can optionally have a double bond and
n and p can be, independent of each other, 0, 1, 2 or 3, with the proviso that n+pxe2x89xa63 and
q is 2
R11 is hydrogen, methyl or hydroxyl and
R12 is hydrogen or an oxo group adjacent to the nitrogen atom,
G is selected from hydrogen, C3-C8-cycloalkyl, methoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, diphenylphosphinoyl or the residues
xe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G1)
and 
and
xe2x80x94SO2xe2x80x94(CH2)rR13xe2x80x83xe2x80x83(G3)
wherein
r is 0, 1 or 2 and
s is 0 or 1,
R13 is hydrogen, methyl, benzyl or phenyl,
indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, dibenzocycloheptenyl, oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl bound directly or over a methylene group,
furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl, chromanonyl, benzopyranyl, chromanyl, quinolyl, isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl, oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, oxobenzocycloheptathienyl, dihydrothienobenzothiepinyl, oxodihydrothienobenzothiepinyl dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydropyridobenzoxepinyl, dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl bound directly or over a methylene group,
R14 is hydrogen, methyl, benzyl or phenyl,
R15 is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,
naphthyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, benzofuryl, benzothienyl, indolyl, indolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl, bound directly or over a methylene group, wherein in formula (I) 
the group NR13R15 can be selected from pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine, Octahydroazocine, piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine, 2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)-dihydroacridine, 1,2,3,4-tetrahydroacridanone, (5H)-dihydrodibenzazepine, (5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[b,f]oxaze-pine or (5H)-tetrahydrodibenzazocine.
The use of compounds in which the labelled substituents in the formula (I) 
have the following meanings are very particularly preferred:
R1 is hydrogen. fluorine, chlorine, bromine, methyl, trifluoromethyl or hydroxy,
R2 and
R3 are hydrogen,
R4 is hydrogen or hydroxy,
k is 0 or 1,
A is selected from C2-C6-alkylene, which is optionally substituted once or twice by hydroxy or fluorine or,
C2-C4-alkylene, which is optionally substituted by fluorine,
C4-alkadienylene, which is optionally substituted by fluorine,
D is selected from C2-C6-alkylene, C2-C6-alkenylene, wherein the double bond can also be to ring E, and C2-C6-alkylene and C2-C6-alkenylene, wherein a methylene unit can be isosterically replaced by O, NH, N(CH3) or CO or an ethylene group can be isosterically replaced by NHxe2x80x94CO and/or COxe2x80x94NH or a propylene group can be isosterically replaced by NHxe2x80x94COxe2x80x94O and/or Oxe2x80x94COxe2x80x94NH,
E is selected from pyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, hexahydroazepine, morpholine and hexahydro-1,4-oxazepine, wherein the heterocyclic ring optionally adjacent to the nitrogen atom, can be substituted by an oxo group,
G is selected from hydrogen, tert-butoxycarbonyl, diphenylphosphinoyl, or one of the residues
xe2x80x94(CH2)rxe2x80x94(CR14R15)sxe2x80x94R13xe2x80x83xe2x80x83(G1)
and 
and
xe2x80x94SO2xe2x80x94(CH2)rR13xe2x80x83xe2x80x83(G3)
wherein
r is 0 or 1 and
s is 0 or 1,
R13 is hydrogen, methyl, benzyl or phenyl,
indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenyl bound directly or over a methylene group,
furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, imidazothiazolyl, benzofuryl, benzothienyl, indolyl, oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzothiazolyl, oxobenzthiazolinyl, benzimidazolyl, oxobenzimidazolinyl, benzofurazanyl, benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl, chromanyl, chromanonyl, benzopyranyl, chromanyl, quinolyl, isoquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl, quinazolinyl, acridinyl, oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl, dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl, oxodihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl, oxobenzocycloheptapyridyl, dihydrodibenzothiazepinyl bound directly or over a methylene group,
R14 is hydrogen, methyl, benzyl or phenyl,
R15 is hydrogen, hydroxy, methyl, benzyl or phenyl,
naphthyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, indolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl bound directly or over a methylene group, wherein in the formula 
the group NR13R15 can be selected from pyrrolidine, piperidine, hexahydroazepine, morpholine, 2,5-diazabicyclo[2.2.1]heptane, indoline, isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline, (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydroacridanone, (5H)-dihydrodibenzazepine, (11H)-dihydrodibenzo[b,e]-oxazepine or (11H)-dihydrodibenzo[b,e]thiazepine and
wherein aromatic ring systems in the substituents can be substituted, independently of each other, by one to three of the same or different substituents from the series halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, C1-C6-alkoxy, which can be entirely or partially substituted by fluorine, can carry benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino or di-(C1-C6-alkyl)-amino, whereby two adjacent groups on the aromatic ring or ring system for an additional ring over a methylenedioxy bridge.
The use of compounds is especially preferred which distinguish themselves in that the labelled substituents in the formula (I) 
have the following meanings:
R1 is hydrogen, fluorine, methyl, trifluoromethyl or hydroxy,
R2 and
R3 are hydrogen,
R4 is hydrogen or hydroxy,
k is 0,
A is ethylene, propylene or butylene which can each be optionally substituted by hydroxy or once or twice by fluorine, or
ethenylene and/or vinylene or
1,3-butadienylene
D is selected from C2-C6-alkylene or C2-C6-alkenylene, wherein the double bond can also be to ring E,
E is selected from pyrrolidine, piperidine, hexahydroazepine or morpholine,
G is selected from benzyl, phenethyl, fluorenylmethyl, anthrylmethyl, diphenylmethyl, fluorenyl or dihydrodibenzocycloheptenyl,
furylmethyl, thienylmethyl, thiazolylmethyl, pyridylmethyl, benzothienylmethyl, quinolylmethyl, phenyl-thienylmethyl, phenyl-pyridylmethyl, dihydrodibenzoxepinyl, dihydrodibenzothiepinyl,
acetyl, pivaloyl, phenylacetyl, diphenylacetyl, diphenylpropionyl, naphthylacetyl, benzoyl, naphthoyl, anthrylcarbonyl, oxofluorenylcarbonyl, oxodihydroanthrylcarbonyl or dioxodihydroanthrylcarbonyl,
furoyl, pyridylcarbonyl, chromonylcarbonyl, quinolylcarbonyl,
naphthylaminocarbonyl, dibenzylaminocarbonyl, benzylphenylaminocarbonyl, diphenylaminocarbonyl, indolinyl-1-carbonyl, dihydrodibenzazepin-N-carbonyl, tetrahydroquinolinyl-N-carbonyl, tetrahydrobenzo[b]azepinyl-N-carbonyl,
methanesulfonyl, phenylsulfonyl, p-toluolsulfonyl, naphthylsulfonyl, quinolinsulfonyl and
diphenylphosphinoyl,
wherein aromatic ring systems can be substituted independently of each other by one to three of the same or different substituents from the series halogen, cyano, C1-C6-alkyl, trifluoromethyl, C3-C8-cycloalkyl, phenyl, benzyl, hydroxy, C1-C6-alkoxy, C1-C6-alkoxy, which can be entirely or partially substituted by fluorine, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, carboxy, C1-C6-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino, mono-C1-C6-alkylamino or di-(C1-C6-alkyl)-amino, wherein two adjacent groups in the ring or ring system can form an additional ring over a methylendioxy bridge.
A series of compounds with the respective substituent definitions are listed as follows in Table 1 for illustration of the use according to the invention without any intended restriction.
Various modes for synthesis of compounds used according to the invention are described in the following for reasons of simplifying reproducability.
Aside from a few exceptions, the optionally combined compounds presently described and used according to the invention are not previously described in the literature. A smaller portion of these compounds overlaps various previously known generic formulae that are very generally defined with respect to structure and which were named at the beginning as prior art. The synthesis methods for the production of the presently used compounds are entirely known to the person skilled in the art either generally from the relevant literature and/or from the prior art publications named at the beginning, also see the literature information referred to below. Consequently, the presently used compounds of the synthesis encompassed by the defined generic formula are easily accessible by analogous methods, as they are described, for example, in the following.
Method (A):
Compounds of formula (I) are obtained by reacting carboxylic acids of formula (II) 
in which R1, R2, R3, A and k have the meaning given above or their reactive derivatives are reacted with compounds of formula (III) 
wherein D, E, G and R4 have the above meanings.
Reactive derivatives of compound (II) can be present, for example, as activated esters, anhydrides, acid halides, especially acid chlorides, or simple low alkyl esters. Suitable activated esters are, for example, p-nitrophenyl ester, 2,4,6-trichlorphenyl ester, pentachlorophenyl ester, cyanomethyl ester, esters of N-hydroxysuccinimide, of N-hydroxyphthalimides, of 1-hydroxybenzotriazol, of N-hydroxypiperidine, of 2-hydroxypyridine or of 2-mercaptopyridine, etc. Anhydrides can be symmetric anhydrides or mixed, as they are obtained, for example, with pivaloyl chloride or with chloroformates. Aromatic (for example chloroformic phenyl ester), araliphatic (for example chloroformic benzyl ester) or aliphatic chloroformates (for example chloroformic methyl ester and/or corresponding -ethyl or -isobutyl ester) can be used for this.
Reaction of compounds (II) with compounds (III) can also be carried out in the presence of condensation agents such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,Nxe2x80x2-carbonyldiimidazol, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, etc. If carbodiimides are used as the condensation agent, reagents such as N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazol, N-hydroxypiperidine, etc. can be advantageously added.
Compounds of formula (III) can be used for reaction as free bases as well as in the form of their acid addition salts. For this, the salts of inorganic acids are to be preferred, i.e. hydrochlorides, hydrobromides or sulfates.
Reaction of compounds (II) or their reactive derivatives with compounds (III) are normally carried out in a suitable, preferably inert solvent. As examples, aromatic hydrocarbons such as benzene, toluol, xylene, halogenated hydrocarbons (for example dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), ethers (for example diethyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate, acetonitrile or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone are to be named. Pure solvents, as well as mixtures of two or more can be used.
The reaction is optionally carried out in the presence of an auxiliary base. Suitable examples for this are alkali metal carbonates (sodium carbonate, potassium carbonate), alkali metal hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate), or organic bases such as, for example, triethylamine, ethyl diisopropylamine, tributylamine, N-methylmorpholine or pyridine. A suitable excess of compound (III) can also be used as a base. If compounds (III) are used in form of their acid addition salts, then it is appropriate to consider the amount of auxiliary base used as equivalent.
The reaction temperatures canxe2x80x94depending on reactivity of the eductsxe2x80x94vary in a wide range. Generally the reaction is carried out at temperatures between xe2x88x9240xc2x0 C. and 180xc2x0 C. preferable between xe2x88x9210xc2x0 C. and 130xc2x0 C., especially at the boiling point of the solvent used.
The starting compounds (II) and (III) are known and/or can be produced according to known methods in an analogous manner. Moreover, the production of representative examples is further described below.
Method (B)
Compounds of formula (I) can be produced by reaction of compounds of formula (I), wherein G is hydrogen and which themselves possess the above-named pharmacological activities such as a cytostatic and/or immunomodulatory activity, as intermediate products as well as end products, with a compound of formula (IV).
Lxe2x80x94Gxe2x80x83xe2x80x83(IV)
in which G has the meaning given above, with the exception of hydrogen, and L is a suitable nucleofuge or reactive group. The type of nucleofuge or reactive group L and the conditions of the reaction are dependent of the nature of group G.
Method (B1)
Compounds of formula (I), in which G, with the exception of hydrogen, has the meaning of (G1) according to the above definition can, aside from method (a), also be produced by reacting compounds of formula (I), wherein G is hydrogen, with a suitable alkylation agent and/or arylation agent of formula (IV), wherein G is an alkyl-, alkenyl-, alkinyl-, cycloalkyl-, aryl-, aralkyl-, heteroaryl- or heteroaralkyl residue according to definition and the leaving group L can be a reactive derivative of an alkohol, for example, a halogen atom such as chlorine, bromine or iodine or a sulfonic acid ester, i.e. for example a methanesulfonyloxy-, trifluoromethanesulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-, p-toluolsulfonyloxy-, p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy residue, etc. A reactive group L can be a terminal epoxide group for example.
The reaction of compounds (I), in which G is a hydrogen, and (IV) is usually conducted in a suitably inert solvent. Such solvents can be, for example, aromatic hydrocarbons (benzene, toluol, xylene), ethers (for example tetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate, acetonitrile, ketones (acetone, ethyl methyl ketone), polar protic solvents such as alcohols (ethanol, isopropanol, butanol, glycol monomethyl ether) or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone. Pure solvents as well as mixtures of two or more can also be used. Preferably, the reactions are carried out in the presence of bases, whereby said bases can be used as in method (a) above If chlorides or bromides are used as compound (IV), the reaction can be accelerated by the addition of alkali metal iodides (sodium iodide, potassium iodide). The reaction temperatures can vary between 0xc2x0 C. and 180xc2x0 C. depending on the reactivity of the educts, but preferable lie between 20xc2x0 C. and 130xc2x0 C.
Method (B2)
Compounds of formula (I), in which G represents an acyl residue, a carbamoyl residue, a sulfonyl residue or a phosphinoyl residue according to the above definition, can also be produced, aside from the above method (a), by reacting compounds of formula (I), in which G is hydrogen, with a carboxylic acid, carbamic acid. sulfonic acid and/or phosphinic acid of formula (V), in which G is an acyl residue, carbarnoyl residue, sulfonyl residue or phosphinoyl residue according to definition,
HOxe2x80x94Gxe2x80x83xe2x80x83(V)
or their derivatives capable of reaction. Preferred derivatives of carboylic acids and/or sulfonic acids (V) which are capable of reaction are symmetric or unsymmetric carboxylic acid anhydrides and/or sulfonic acid anhydrides or acyl- and/or sulfonyl halides, especially acyl- and/or sulfonyl chlorides. Preferably, derivatives of carbamates and/or phosphinic acids which are capable of reaction are the carbamoyl halides and/or phosphinyl halides, especially carbamyl- and/or phosphinyl chlorides. The reaction of the acids (V) and/or their reactive derivatives with compounds (I), in which G is hydrogen, preferably occurs in the presence of auxiliary bases in solvents and under conditions as they are described in method (A).
Method (B3)
Compounds of formula (I), in which G represents a carbamoyl residue according to the definition G2 with r=0. i.e. the group 
can also be produced, aside from the methods (A) and (B2), by reacting compounds of formula (I), in which G is hydrogen with a carbonyl group transmitter to an intermediate product and subsequently reacting this directly with a primary or secondary amine with the formula (VI)
Hxe2x80x94NR13R15xe2x80x83xe2x80x83(VI)
in which R13 and R15 and/or the group xe2x80x94NR13R15 have the meanings according to the above definitions without having to purify or isolate the intermediate product. Trichloromethylcarbonate (triphosgene) and carbonyldiimidazol have been proven as particularly reactive carbonyl group transmitters. The reaction of compounds of formula (I), wherein G is hydrogen, with triphosgere and/or carbonyldiimidazol are typically conducted in an absolute, inert solvent in the presence of a tertiary, organic amine as an auxiliary base in such a manner that the solution of compounds (I) and the auxiliary base are slowly poured into a solution of an equivalent amount of carbonyl group transmitter. Thereby, the reaction requires molar ratios of 1:1 for the reaction of compound (I) and carbonyldiimidazol, and, in contrast, a ratio of 1:0.35 for the use of triphosgene. After complete reaction of the components to the intermediate product, compound (VI) is added in stochiometric amounts or in excess as a solution or a solid and the reaction is tropically completed at elevated temperature. Suitable inert solvents are, for example hydrocarbons such as hexane, heptane, benzene, toluol, xylene, chlorinated hydrocarbons (for example dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), ethers (for example diethyl ether, tetrahydrofuran, dioxane), esters such as ethyl acetate, butyl acetate, acetonitrile or polar aprodic solvents such as formamide or dimethylformamide. Pure solvents as well as mixtures can be used diversely. Sometimes it is of advantage to carry out the first partial reaction at low temperature in a low-viscosity, highly-volatile solvent and to remove the solvent after formation of the intermediate and replace it by a higher boiling solvent. Amines such as for example triethylamine, ethyl diisopropylamine, tributylamine, N-methylmorpholine or pyridine are suitable as auxiliary bases. If compounds (I) or (VI) are used as salts, the amount of the auxiliary base is increased accordingly. The reaction temperatures can lie in between xe2x88x9240xc2x0 C. and 50xc2x0 C. for the first partial reaction, preferably at 0xc2x0 C. bis 30xc2x0 C., and between 0xc2x0 C. and 150xc2x0 C. for the second partial reaction, preferably at 20xc2x0 C. bis 120xc2x0 C.
Method (B4)
Compounds of formula (I), in which G represents a carbamoyl residue according to the definition G2 with r=0 and R15=hydrogen, i.e. a group 
can also be produced. aside from methods A, B2 and B3, by reacting the compounds of formula (I) in which G is hydrogen, with an isocyanate of formula (VII) in which R13 has the meaning according to the above definition
Oxe2x95x90Cxe2x95x90Nxe2x80x94R13xe2x80x83xe2x80x83(VII)
Reaction of the compounds of formula (I), in which G is hydrogen, with the isocyanates of formula (VII) are conducted thereby in an absolute, inert solvent which can be a hydrocarbon such as pentane, hexane, heptane, benzene, toluol, or xylene, chlorinated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene), ethers (for example, diethyl ether, tetrahydrofuran, dioxane), esters such as ethyl acetate, butyl acetate, or polar aprotic solvents such as formamide or dimethylformamide. Mixtures of various solvents can also be used. Thereby, the reaction temperatures can vary, in the region from xe2x88x9220xc2x0 C. to 150xc2x0 C., but preferably lie at 20xc2x0 C. to 100xc2x0 C.
The above-named intermediate products in the form of compounds according to formula (I), wherein G is hydrogen, which have the above-mentioned activities, such as for example a cytostatic activity in an analogous way to the end products themselves, are suitable for the production of a multitude of end products through the synthesis methods B1-B4.
They themselves can, in principle, be produced according to method A by reacting a carboxylic acid of formula (II) with amines of formula (III) in which G is hydrogen as described above. However, since the compounds of formula (III) with hydrogen as G represent xcex1,xcfx89-diamines, the formation of product mixtures is always to be expected in their reaction with carboxylic acids (II) or their reactive derivatives making a subsequent separation necessary.
In contrast, compounds of formula (I), in which G is hydrogen, are essentially more advantageously produced from other compounds of formula (I), in which G is a selectively cleavable group under mild conditions, i.e. corresponds to a nitrogen protective group.
Among the compounds according to formula (I) with tumor growth inhibiting properties, compounds are particularly suitable for this in which G represents a benzyl group, a 4-methoxybenzyl group, a diphenylmethyl croup, a triphenylmethyl group, a benzloxycarbonyl group, a methoxy- and/or ethoxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonyl group or a trifluoroacetyl group. For example, compounds according to formula (I) with benzyl, diphenylmethyl, triphenylmethyl or benzyloxycarbonyl groups can already be catalytically transformed into the compounds of formula (I) with hydrogen as G at room temperature under mild conditions with elementary hydrogen or by transfer hydration. Compounds of formula (I) with a 4-methoxylbenzyl group are transformed into compounds of formula (I) with hydrogen as G by selective oxidation with ammonium-cer(IV)-nitrate. The cleavage of simple alkoxycarbonyl groups such as the methoxy- or ethoxycarbonyl group as well as the trifluoroacetyl group as G in compounds of formula (I) succeed by alkali hydrolysis under mild conditions without cleaning the A and D linked amide function. This is suitably valid for the cleavage of the triphenylmethyl group and the tert-butoxycarbonyl group as G in compounds of formula (I), which occurs in acidic medium under mild conditions. Finally compounds of formula (I) with an allyloxycarbonyl group as G can be converted into such with hydrogen as G in neutral medium with palladium catalyst. All these methods are fully familiar to the person skilled in the art, and are furthermore also documented in monographs (see for example Greene, Wuts, Protective Groups in Organic Synthesis, New York, 1991).
Method C
Compounds of formula (I), in which R4 is an alkyl, alkenyl, alkinyl or cycloalkyl residue according to the above definition can also be produced, aside from the methods A and B, by reacting compounds of formula (I), in which R4 is hydrogen, with a suitable alkylation agent of formula (VIII)
Lxe2x80x94R4xe2x80x83xe2x80x83(VIII)
in which R4 is an alkyl, alkenyl, alkinyl or cycloalkyl residue according to the above definition and L is a suitable nucleofuge, i.e. for example a halogen atom such as chlorine, bromine or iodine or a sulfonic acid ester of an alcohol. Preferred sulfonic acid esters (VIII) contain a methylsulfonyloxy residue, trifluoromethanesulfonyloxy-, p-toluolsulfonyloxy-, p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy residue as L. As an amide alkylation in the presence of tertiary amino groups, this reaction requires the use of strong auxiliary bases such as potassium-tert-butylate, sodium hydride, potassium hydride or butyl lithium in aprotic, inert solvents. Such solvents can be for example aliphatic or aromatic hydrocarbons (pentane, hexane, heptane, benzene, toluol), ethers (for example, tetrahydrofuran, dioxane) or polar solvents such as dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone. Depending on the reactivity of the educts, the reaction temperatures can lie between xe2x88x9240xc2x0 C. and 140xc2x0 C. preferably between xe2x88x9220xc2x0 C. and 80xc2x0 C.
Method D
Compounds of formula (I) in which A is a saturated alkylene group can also be produced, aside from methods A, B and C, by hydrating compounds of formula (I) in which A is an unsaturated group according to the above definition, i.e. an alkenylene group or alkadienyl group with elementary hydrogen in the presence of a suitable catalyst. This method is also applicable when the compounds of formula (I) with an unsaturated group A in the molecule simultaneously contain a principally hydrogenolytically cleavable group B, i.e.xe2x80x94as already mentioned abovexe2x80x94a benzyl croup, a diphenylmethyl or triphenylmethyl group. In the selection of the conditions, especially the solvent, the temperature and the acid additive in the reaction mixture, the reaction can be controlably driven either to a selective saturation of the Cxe2x80x94C multiple bond(s) in the structural element A or to a simultaneous cleavage of the benzyl, diphenylmethyl or triphenylmethyl residue G under formation of the compounds of formula (I) with hydrogen as G.
The hydration is preferably carried out in barely polar, aprotic solvents for selective hydration of one or more Cxe2x80x94C multiple bonds of group A in the compounds of formula (I) according to the invention while attaining a simultaneously present hydrogenolytically cleavable benzyl, diphenylmethyl or triphenylmethyl residue as the structural element G. Esters such as ethyl acetate, propyl acetate, butyl acetate or ethers such as tetrahyodrofuran, dioxane or ethylene glycol dimethyl ether can be used. Compounds of formula (I) to be hydrated can be present as a free base or entirely or partially in the form of a salt by addition of a sub-maximal to a maximal stochiometric amount of a strong acid, preferably a mineral acid. As a catalyst, palladium is suitable in various proportional amounts from 1, 3, 5 or 10% on solid supports such as activated carbon, activated aluminum oxide or calcium carbonate. The hydration is carried out under normal pressure and at a temperature of 10 to maximally 30xc2x0 C., preferably at 20 to 25xc2x0 C. and interrupted after consumption of the amount of hydrogen calculated for the saturation of the multiple bonds.
In contrasts for simultaneous cleavage of the multiple bonds in A and the cleavage of a benzyl, diphenylmethyl or triphenylmethyl group as G in the compound of formula (I), polar, aprotic solvents are used such as methanol, ethanol isopropanol, methoxyethanol or water or mixtures thereof, whereby a considerable excess of a strong acid compared to the stochiometric salt formation, preferably a mineral acid such as concentrated hydrochloric acid or sulfuric acid is simultaneously added. The molecular ratio of substrate/acid can lie in the range of 1:2 to 1:10 thereby, preferably between 1:3 and 1:5. The same catalysts which are mentioned above in connection with the selective hydration are suitable as catalysts. The hydration is carried out under normal pressure or slightly increased hydrogen pressure of 2 to 3 bar, preferably under normal pressure, until the termination of the uptake of hydrogen Depending on uptake speed, the reaction temperature can vary between 10 and 50, 70 or 80xc2x0 C. as a function of the boiling point of the solvent and/or solvent mixture and employed pressure. If, for example, the reaction is carried out in ethanol or ethanol/water under normal pressure, the reaction temperature preferably lies between 40 to 60xc2x0 C.
The compounds of formula (I) produced according to the method (A), (B1) to (B4), (C) or (D) can be isolated and purified in a known manner, for example by subjecting the residue after distillation of the solvent to partition, extraction, re-precipitation or re-crystallization or another purification method. For this, column chromatography on a suitable support or preparative, middle or high pressure liquid chromatography are preferred for this.
The compounds (I) are first normally obtained in form of their free bases or their hydrates or solvates, depending on the type of isolation and purification. Their addition salts with pharmaceutically suitable acids are obtained in a typical manner by converting the base with the desired acid in a suitable solvent. Depending on the number of basic centers of compound (I), one or more equivalent acids per mole of base can be bound.
Suitable solvents are, for example, chlorinated hydrocarbons such as dichloromethane or chloroform; ethers such as diethyl ether, dioxane or tetrahydrofuran; acetonitrile, ketones such as acetone or ethyl methyl ketone; esters such as methyl acetate or ethyl acetate or low molecular alcohols such as methanol, ethanol or isopropanol, and water. Pure solvents as well as mixtures of two or three solvents can also be used. The salts can be isolated by crystallization, precipitation or the evaporation of the solvent. Thereby, they optionally accumulate as hydrates or solvates.
The bases can be recovered from the salts by alkalization, for example with aqueous ammonia solution, alkali carbonate or diluted sodium hydroxide solution.
The following listed compounds and/or their pharmaceutically acceptable salts, if not already concretely labelled as such, are particularly preferred.
N-[2-(1-benzylpiperidin-4-yl)-ethyl]-3-(pyridin-3-yl)-propionamide,
N-{2-[1-(2-phenylethyl)-piperidin-4-yl]-ethyl}-3-(pyridin-3-yl)-propionamide
N-{2-[1-(4-phenylbutyl)-piperidin-4-yl]-ethyl}-3-(pyridin-3-yl)-propionamide
N-{2-[1-(4-hydroxy-4-phenylbutyl)-piperidin-4-yl]-ethyl}-3-(pyridin-3-yl)-propionamide
N-[2-(1-diphenylmethylpiperidin-4-yl)-ethyl]-3-(pyridin-3-yl)-propionamide,
N-[3-(1-diphenylmethylpiperidin-4-yl)-propyl]-3-(pyridin-3-yl)-propionamide,
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-propionamide,
N-[2-(1-benzylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,
N-{4-[1-(2-phenylethyl)-piperidin-4yl]-butyl}-3-(pyridin-3-yl)-acrylamide
N-{4-[1-(4-biphenylmethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide
N-{4-[1-(1-naphthylmethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide
N-{4-[1-(1-anthrymethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide
N-{4-[1-(Cyclohexylphenylmethyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide
N-{4-[1-(10,11-dihydro-5H-dienzo[a,d]cycloheptene-5-yl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide
N-[2-(1-diphenylmethylpiperidin-4-yl)-ethyl]-3-(pyridin-3-yl)-acrylamide,
N-[3-(1-diphenylmethylpiperidin-4-yl)-propyl]-3-(pyridin-3-yl)-acrylamide,
N-[5-(1-diphenylmethylpiperidin-4-yl)-pentyl]-3-(pyridin-3-yl)-acrylamide,
N-[6-(1-diphenylmethylpiperidin-4-yl)-hexyl]-3-(pyridin-3-yl)-acrylamide,
N-[4-(1-diphenylmethylpiperidin-4-yl)butyl]-5-(pyridin-3-yl)-2,4-pentadiene acid amide,
N-(4-{1-[bis-(4-fluorophenyl)-methyl]-piperidin-4-yl}-butyl)-3-(pyridin-3-yl)-acrylamide,
N-(4-{1-[bis-(2-chlorophenyl)-methyl]-piperidin-4-yl}-butyl)-3-(pyridin-3-yl)-acrylamide,
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(2-fluoropyridin-3-yl)-acrylamide,
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(6-fluoropyridin-3-yl)-acrylamide,
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pryridin-3-yl)-acrylamide,
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride or,
N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide methanesulfonate.